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Original Article
Eur J Gen Med 2013;10(1):26-31
Heart Failure: Discrepancy Between NYHA Functional
Classification, Serum NT-pro Brain Natriuretic Peptide
and Ejection Fraction
Adil Hassan Alhusseiny1, Marwan Salih Mohamad Al-Nimer2, Ismail Ibrahim Latif3, Ahood Khaleel Ibrahim4
ABSTRACT
This study aimed to look for the discrepancy between the laboratory investigation (determination of serum NT-proBNP), electrophysiological assessment (echocardiogram and Doppler study) and clinical assessment of known cases of congestive heart failure.
This study conducted in the college teaching hospital from January to October 2011. This study is a cross-sectional in a cohort of
patients with heart failure. Known cases of congestive heart failure and healthy subjects served as control group were enrolled
in this study. Patients were assessed clinically according to the New York Heart Association (NYHA) functional classification, echocardiography by ejection fraction and laboratory by determination of NT-proBNP).Student's "t" test (one paired, two tailed) and
simple correlation test were used in data analysis. The results of 169 patients enrolled in this study showed that serum levels of
NT-proBNP did not match the NYHA functional classification of heart failure. Serum NT-proBNP was significantly inversed-correlated (r = -0.339, p < 0.001) with the serum ejection fraction and inconsistently related to the E/A ratio assessed by Doppler study.
It concludes that serum NT-proBNP level is well correlated with ejection fraction and not well matched the functional disabilities
of longstanding heart failure.
Key words: NT-proBNP, Heart failure, ejection fraction
Kalp yetmezliği: NYHA Fonksiyonel Sınıflandırma, Serum NT-probrain Natriüretik Peptid ve Ejeksiyon
Fraksiyonu Arasındaki tutarsızlık
ÖZET
Bu çalışma konjestif kalp yetmezliği bilinen olgularda laboratuar inceleme (serum NT-pro BNP değerlendirmesi), elektrofizyolojik
değerlendirme (ekokardiyografi ve Doppler çalışması) ve klinik değerlendirme arasındaki tutarsızlığı araştırmayı amaçlamıştır.
Bu çalışma Ocak-Ekim 2011 tarihleri arasında üniversite araştırma hastanesinde yapılmıştır. Bu, kalp yetmezliği olan hastalardan
oluşan bir kohortta kesitsel bir çalışmadır. Konjestif kalp yetmezliği bilinen vakalar ve sağlıklı bireyler bu çalışmaya kontrol grubu
olarak katılmışlardır. Hastalar, klinik olarak New York Kalp birliğinin (NYHA) fonksiyonel sınıflaması, ekokardiyografik olarak
ejeksiyon fraksiyonu ve laboratuar inceleme olarak NT-pro BNP değerine göre değerlendirilmişlerdir. Veri analizi Student’s t testi
(bir çift, iki uçlu) ve basit korelasyon testi kullanılarak yapılmıştır. Çalışmaya alınan 169 hastanın sonuçları göstermiştir ki serum
NT- pro BNP düzeyleri kalp yetmezliğinin NYHA fonksiyonel sınıflaması ile uyumlu değildir. Serum NT-pro BNP düzeyleri anlamlı
şekilde ejeksiyon fraksiyonu ile ters orantılıdır (r = -0.339, p < 0.001) ve Doppler çalışması ile değerlendirilen E/A oranı ile tutarsız
şekilde ilişkilidir. Sonuç olarak serum NT-pro BNP düzeyleri ejeksiyon fraksiyonu ile iyi koreledir ve uzun süren kalp yetmezliğinin
fonksiyonel kısıtlamaları ile iyi uyum göstermemektedir.
Anahtar kelimeler: NT-pro BNP, kalp yetmezliği, ejeksiyon fraksiyonu
Diyala University, College of Medicine, Diyala, Iraq, 2 Al-Mustansiriya University,
College of Medicine, Department of Pharmacology, Baghdad, Iraq, 3Diyala University, College of Medicine, Department of Microbiology, Diyala, Iraq, 4Department
of Laboratories: Clinical Biochemistry Ibn Al-Bitar Specialized Center for Cardiac
Surgery
1
Received: 27.07.2012, Accepted: 30.07.2012
European Journal of General Medicine
Correspondence: Professor Dr. Marwan S.M. Al-Nimer
Department of Pharmacology College of Medicine, Al-Mustansiriya University
P.O. Box 14132, Baghdad, Iraq
E-mail: [email protected]
Heart failure, NT-proBNP
INTRODUCTION
MATERIALS AND METHODS
Brain natriuretic peptide (BNP) released from cardiac
ventricular myocytes in response to volume or pressure
overload. Rapid measurement of plasma BNP or NTproBNP improved the diagnostic accuracy of heart failure
(HF) exacerbations (1). Large amounts of proBNP can be
detected in plasma of healthy subjects and in particular
of patients with heart failure. Plasma concentrations of
BNP and amino-terminal pro-B-type natriuretic peptide
(NT-proBNP) are more closely related to measurements of
cardiac structure, function and to cardiovascular prognosis than ANP or other circulating neurohumoral markers of
cardiac disease (2). Natriuretic peptides were known to
decrease following medical therapy of HF, suggesting the
role of their measurement in monitoring inpatient disease
progression and outpatient medical programs (3). Atrial
fibrillation was associated with high BNP level in patients
with reserved left ventricular ejection fraction, therefore the measurement of BNP concentration in patients
with atrial fibrillation allowed to diagnose HF at early
stages (4). In hypertension, the Left atrial enlargement,
rather than left ventricular hypertrophy was correlated
with elevated plasma BNP that produced by increased
left ventricular after load (5). Determination of BNP is a
useful laboratory test in identifying left ventricular systolic dysfunction in patients suffered from exacerbation
of chronic obstructive pulmonary disease (6). Prastaro et
al (7) demonstrated NT-pro-BNP cut-off of 1480 pg/ml indicated left atrium dysfunction with 89% specificity and
54% sensitivity, in congestive heart failure patients with
severely impaired systolic function, NT-pro-BNP levels reflect left atrium and ventricle dysfunction. Preoperative
assessment of NT-proBNP level in coronary artery bypassing grafting (CABG) patients could be a valuable diagnostic method for predicting several postoperative complications, especially pulmonary outcomes and requirement
for hemodynamic support. The NT-proBNP level was a
predictor of postoperative prolonged mechanical ventilation, respiratory failure, atrial fibrillation, intra-aortic
balloon pump counterpulsation use, inotropic support
and postoperative platelet transfusions (8). BNP level is
not affected by the criteria of metabolic syndrome while
diabetes mellitus causes an increase BNP level (9).
This study was done in the college teaching hospital
from January to October 2011. This study was approved
by an institutional review committee and informed consent was obtained from each patient prior to enroll in
the study. This study designed as a cross sectional in
cohort patients with heart failure and healthy subjects
(served as control group). The criteria of inclusion of
patients group were; known cases treated-heart failure,
≥ 3 months duration, evidence of risk factors including
ischemic heart disease, hypertension, cardiomyopathy
valvular heart disease and diabetes mellitus. The criteria of exclusion are: acute left ventricular failure,
chronic obstructive lung history, history of cardiac surgery or pacing (because the level of NT-proBNP may be
increased), renal failure, terminal illnesses. The patients were allocated randomly using randomized tables
from heart failure patients who attended the college
teaching hospital for follow up. The sample size of patients was determined using the following formula (10):
The aim of this study was to explore the discrepancy
between the laboratory investigation (determination of
NT-proBNP), electrophysiological assessment (echocardiogram and Doppler study) and clinical assessments of
known cases of congestive heart failure.
27
n={μ√([π(1-π) ] )+v√([π◦(1-π◦) ] )}2/ (π-π◦)2
Where
n = required minimum sample size
π = proportion of interest which proposed in this study
0.7
π◦= null hypothesis proportion which equal to 0.5
μ= one side percentage point of normal distribution corresponding to 100% - the significant power. In this study
the power 85%, (100%-85%) =15% and μ=1.036
v= percentage of the normal distribution corresponding to the required (two-sided) significant level. In this
study the significant level of 5% was considered, v=1.96
Therefore the estimated sample size should be more
than 53 patients
The control group included an apparent healthy subjects with normal limits electrocardiographic, echocardiographic , chest X-ray and laboratory investigations
(complete blood picture, erythrocyte sedimentation
rate, fasting serum glucose, serum creatinine and lipid
profile). Each patient was examined, assessed and categorized according to the New York Heart Association
Functional Classification (NYHA) into four classes: I (no
symptoms), II (mild symptoms), III (marked limitation)
and IV (severe limitations). The anthropometric mea-
Eur J Gen Med 2013;10(1):26-31
Alhusseiny et all.
Figure 1. Relationship between ejection fraction (%)
and serum level of NT-proBNP(pg/ml) in patients with
heart failure.
Figure 2. Distribution of cases according to the NYHA
classification of heart failure and their corresponding
ejection fraction.
surements including weight (kg), height (m) and the calculated body mass index (kg/m2), electrocardiogram,
echocardiography (for the diagnostic and prognostic
purposes) and Doppler study (determination the E/A ratio) were obtained. Peripheral venous blood was drawn
immediately after admission into tubes until clot formation, then the samples were centrifuged at 2500 rpm for
10 min, and the sera were frozen and stored at -70oC
until analyzed for determination of NT-proBNP. The serum level of proBNP (a biomarker of heart failure) was
determined in the laboratories of Specialized Center for
Cardiac Surgery using the technique of Enzyme Linked
Fluorescent Assay (VIDAS NT-proBNP automated test
for use on the VIDAS instrument, Biomerieux, France).
The principle of this assay is a one step immunoassay
sandwich method with a final fluorescent detection
(ELFA) and the range of measurement is 20-25000 pg/
ml). Levels below 100 pg/ml indicate no heart failure,
100-300 pg/ml suggest heart failure is present, >300
indicate mild heart failure, > 600 ml indicate moderate heart failure and >900 pg/ml indicate severe heart
failure.
RESULTS
Statistical analysis
The results expressed as absolute number, percent,
mean ± SD. The data analyzed using Student's "t" test
(one paired, two tailed) and simple correlation test taking the p ≤ 0.05 as lowest limit of significance.
Eur J Gen Med 2013;10(1): 26-31
One hundred and sixty nine (70 male and 99 female)
known cases of congestive heart failure and 22 healthy
subjects (11 male and 13 female) serve as control group
were admitted in this study. The characteristics of the
study presented in Table 1. Hypertension (67.5%) and diabetes mellitus (33.7%) are the most common associated illnesses followed by myocardial infarction (26%). No
identified cause or associated illnesses were observed
in 35 out of 169 (20.7%) patients. Table 2 shows the discrepancy in the level of NT-proBNP taking in considerations the NYHA classification of heart failure and the
cut-off level of NT-proBNP for the severity of heart failure. Fifty seven cases (33.7%) were clinically assessed as
class 1(mild) heart failure and 18 cases out of this number (31.5%) have serum NT-proBNP level less than 100
pg/ml. In class 2 (mild) heart failure 5 out of 27 (18.5%)
cases have serum NT-proBNP level less than 100pg/ml.
On the other hand, patients classified clinically as class
3 (moderate) heart failure have serum NT-proBNP level
exceeded the level 900 pg/ml in 29 out of 33 (87.9%)
patients. In healthy subjects, 2 out of 24 subjects have
serum level of NT-proBNP more than 300 pg/ml (8.4%).
Further analysis revealed that serum levels of NT-proBNP
did not match the NYHA classification of heart failure if
the cut-off level of NT-proBNP is taken in consideration
according to the manufacturer (Table 3). Figure 1 shows
that whatever the NYHA class of heart failure, the ejection fraction is significantly correlated (r = -0.339, p <
0.001) with the serum NT-proBNP level. The mean value
of ejection fraction of class 4 is significantly less than
28
Heart failure, NT-proBNP
Table 1. Characteristics of the study
Number 169
Gender (M:F)70:99
Age (year)61.4±11.9
Smokers41 (24.3%)
Family history1 (0.6%)
BMI21.94±3.358
History of :
Hypertension114 (67.5%)
Diabetes mellitus57 (33.7%)
Hyperlipidemia18 (10.7%)
Atrial fibrillation
6 (3.6%)
History of:
Stable angina26 (15.4%)
Unstable angina4 (2.4%)
Myocardial infarction
44 (26%)
Arrhythmias3 (1.8%)
corresponding values of class 3, 2 and 1. Moreover the
distribution of cases according to the NYHA classification showed overlap in the values of ejection fraction in
each class (Figure 2). Doppler study revealed that E/A
ratio was more than 1.5 in three patients with serum NTproBNP level 300-600 pg/ml and less than 1.0 in seven
patients; three of them with serum NT-proBNP 300-600
pg/ml and the other four patients with serum level of
NT-proBNP of 600-900 pg/ml.
DISCUSSION
The results of this study show that the serum levels
of NT-proBNP are not well match the classes of NYHA
functional classification of heart failure but significantly correlated with reduced ejection fraction. The primary outcome measures of this study showed that the
overall mean level of serum NT-proBNP is progressively
increased with NYHA functional classification of heart
failure and significantly increased with reduced ejection
fraction (%). On the other hand, the secondary outcome
measures revealed that the cut-off level of serum NTproBNP that pointed the presence of heart failure or the
severity of heart failure did not well matched. It is well
known that serum level of inactive N-terminal proBNP
(NT-proBNP) provides primarily information regarding
the filling pressures in the heart and its determination
to diagnose heart failure at an early stage cannot be
recommended because their specificity is too low; the
serum level of NT-proBNP is affected by age, gender,
body mass index, renal function, and pulmonary capacity (11). Most patients who involved in this study had history and presented with components of metabolic syndrome e.g. high blood pressure, diabetes mellitus and
obesity which may altered the serum level of NT-proBNP.
Recently, there is evidence that low level of NT-proBNP
may be attributed to the metabolic syndrome components (12) and a relationship between metabolic components and lower plasma NT-proBNP concentration was
also reported (13). Studies indicate a dual use for NTproBNP, both to exclude acute heart failure (where NTproBNP concentrations < 300 ng/L have a 98% negative
predictive value), as well as to identify the diagnosis
of heart failure (14). The results of this study show significant high serum level of NT-proBNP reported in class
III and IV indicating that this test is limited to the severe longstanding heart failure. Previous study reported
that NT-proBNP was significantly higher in complicated
heart failure patients than in heart failure patients
(15). It was significantly higher in heart failure grade
III patients complicated with cerebral infarction. In this
study neither the severity of heart failure as assessed
by NYHA nor the E/A ratio assessed by Doppler study
are related to the level of NT-proBNP. Al Bannay and
Husain (16) found that the tissue Doppler imaging (TDI)
Table 2. Distribution of cases according to the NYHA classification and the serum level of NT-proBNP according to
the instruction of the NT-proBNP manufacturer
NYHA classification
Class 1 (mild)
Class 2 (mild)
Class 3 (moderate)
Class 4 (severe)
Serum BNP(pg/ml)
29
Normal (≤100 pg/ml)
(n:23) 18
05
0
0
48.04±27.93
Suspected
(100-300 pg/ml)
(n:17) Mild
(300-600 pg/ml)
(n:22) Moderate
(600-900 pg/ml) (n:19) Severe
(>900 pg/ml)
(n:88)
08
09
0
0
177.0±53.72
09
10
03
0
407.5±63.9
04
14
01
0
720.9±90.1
18
27
29
14
4116.3±4685.2
Eur J Gen Med 2013;10(1):26-31
Alhusseiny et all.
Table 3. Distribution of cases according to the NYHA classification and their corresponding serum level of NTproBNP
NYHA classification
Serum NT-proBNP (pg/ml)
Ejection fraction (%)
Healthy subjects (n=24)
76.3 ±99.0
Class 1 (mild)(n=57)878.1±1090.1*55.43±8.48
Class 2 (mild)(n=65)1418.2±3197.7*52.88±8.03
Class 3 (moderate)(n=33)3969.5±4168.8*48.22±10.22†‡‡
Class 4 (severe)(n=14)8270.2±6116.9*†‡+43.42±14.58††
The results are expressed as mean±SD, *p < 0.001 compared with healthy subject, †p <0.001, ††p< 0.01 compared with class 1, ‡p < 0.001, ‡‡ p < 0.05 compared with
class 2, +p< 0.05 compared with class 3
maintained a steady positive correlation with both NYHA
functional class and the Pro-BNP titer in hypertensive
patients presented with dyspnea. Significant correlation
between ejection fraction and NT-proBNP is observed
in this study. ProBNP tended to be decreased in heart
failure with preserved ejection fraction and increased
with reduced ejection fraction (17). Even in absence of
heart failure, proBNP level is strongly correlated with
the decrease of ejection fraction in patients with left
ventricular systolic dysfunction (18). Limitations of
this study include the associated risk factors, variable
etio-pathological factors of heart failure and anti-heart
failure medications. Nevertheless, the results of this
study pointed out that using cut-off level of serum NTproBNP in longstanding heart failure is not sufficient to
assess the patient and clinical examinations as well as
the echocardiographic study are required for assessment. This is the first report that highlights the discrepancy between laboratory findings, echocardiographyic
study and clinical assessment of known treated cases
of heart failure. Most studies were carried on acute or
emergency heart failure or looking for the conditions
that associated with high serum or plasma level of NTproBNP. Further study is recommended to assess serum
NTproBNP level in chronic heart failure in absence of
confounding (risk) factors. It concludes that single determination of serum NT-proBNP provides a useful tool
in severe longstanding heart failure patients with reduced ejection fraction.
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